Steve Connor

On July 1st. the journal Nature, published three reports that described genetic differences between people with schizophrenia and the rest of us. Nature held a big press conference, at the World Conference of Science Journalists, Many of the individual institutions involved in the studies also issued press releases. As so often in press releases, descriptions like “landmark”, “major step forward” and “real scientific breakthrough” were used liberally.

In short, there is no simple genetic basis for schizophrenia. The pooled results of the three studies gave 8,014 cases and 19,090 controls. A huge amount of genetic analysis was involved. Many thousands of small genetic differences were found between the schizophrenics and the controls, but no single mutation alone had much effect. There could be even more, because it is still not possible to sequence the entire genome of so many people. . In total, the effects of the many small differences might account for 30 percent of the disease risk. That’s more than the few percent that could be predicted before, though it’s still well short of the 70 or 80 percent figure that is often quoted for the genetic component of schizophrenia.

What is observed is a correlation between differences in the genome and having schizophrenia. The results don’t tell us directly about the cause of schizophrenia, and they don’t even (so far anyway) tell us much about the mechanisms that give rise to schizophrenia.

The headline sounds pretty hyped up to me, but headlines are often written by sub-editors, not by the author of the article. The article itself seems to be a pretty straight account that uses mostly quotations from the press releases. And it is accompanied by an irrelevant picture of a brain image, that’s alleged to show areas of the brain that contain dopamine receptors, though the work being discussed shows exactly that It’s not just a matter of a disorder in a transmitter system.. So the article is OK but it doesn’t contribute anything itself.

The fact of the matter is that the results of the gargantuan effort put into this study is to show how enormously complicated the problem is and just how little we understand, The prospect of inventing ‘cures’ looks almost hopeless in the face of such complexity. Nobody said it would be easy, but it has turned
out to be even harder than pessimists guessed. I would prefer a report that conveyed this reality better than the press releases do, and better than most of the hundreds of newspaper reports based on the press releases. There is one such report, that in the New York Times.

The journal Nature held a big press conference in London Wednesday, at the World Conference of Science Journalists, to unveil three large studies of the genetics of schizophrenia. Press releases from five American and European institutions celebrated the findings, one using epithets like “landmark,” “major step forward,” and “real scientific breakthrough.” It was the kind of hoopla you’d expect for an actual scientific advance.

It seems to me the reports represent more of a historic defeat, a Pearl Harbor of schizophrenia research.

The defeat points solely to the daunting nature of the adversary, not to any failing on the part of the researchers, who were using the most advanced tools available. Still, who is helped by dressing
up a severely disappointing setback as a “major step forward”?

The principal news from the three studies is that schizophrenia is caused by a very large number of errant genes, not a manageable and meaningful handful.

The rationale behind the long search for schizophrenia genes was entirely justifiable. Since schizophrenia is highly heritable, it must have a strong genetic component. And it has long seemed possible that the responsible genetic variants underlying most common diseases would also be common. Natural selection gives us strong protection against diseases that strike before the age of reproduction. But its power to eliminate harmful genes is thought to wane sharply thereafter. So bad versions of genes that are bad only late in life could build up in the population, explaining why the common diseases that strike later in life are so common.

And if researchers could identify the few major variants assumed to underlie each of these common diseases, from schizophrenia to heart disease to cancer, they could devise drugs to offset the genes’ effects.

But nature is often a lot more complex than assumed. It now seems that the arm of natural selection is far longer than thought. It has reached way beyond our reproductive years and zapped most harmful genetic variants before they could get to be common in the population. That leaves relatively uncommon variants, lots and lots of them in each case, as the genetic cause of each common disease.

In the last few years gene hunters in one common disease after another have turned up a few causative variant genes, after vast effort, but the variants generally account for a small percentage of the overall burden of illness. With most common diseases, it turns out, the disease is caused not by ten very common variant genes but by 10,000 relatively rare ones.

Today it’s the turn of schizophrenia researchers to make the same discovery, though one perhaps more to be expected since schizophrenia is not good for reproduction.

Schizophrenia too seems to be not a single disease, but the end point of 10,000 different disruptions to the delicate architecture of the human brain.

Yes, that discovery is a landmark. The kind that says you have 10,000 miles yet to go.

The march of science is not direct but two steps forward, one step back. This was the step back. But it was a completely necessary one. So the press release writers could have cast it as a noble defeat, were words like defeat a part of their vocabulary, or frankness their masters’ priority.

This account may sound a bit pessimistic, but it also seems to me to be the most realistic of the lot.

Schizophrenia is not alone in proving to be a lot more complicated than one would have hoped. One of the most interesting outcomes of the genomic age has been to show that far simpler conditions than schizophrenia turn out to be not so simple after all. The simplest genetically transmitted diseases are those caused by mutation of a single amino acid in a single protein of known function. For example, one of the best understood receptors is the type of acetylcholine receptor that is responsible for transmitting an impulse from a motor nerve to a muscle cell, Curare blocks them and so paralyses voluntary movement, A rare form of muscle weakness, slow channel congenital myasthenic syndrome (SCCMS), is caused when one of the amino acids in the protein mutates. But it has turned out that there is not just one mutation. It would be nearer to the truth to say that each family that suffers from the disease has its own mutation. Each of the mutations has a rather similar effect on the function of the protein, but there is not just one SCCMS but dozens.

The same is true of mutations in the glycine receptor that cause the rare congenital condition, ‘startle disease’ (posh name, hyperekplexia), The glycine receptor mediates inhibitory actions in the spinal cord. It is blocked by strychine, Strychnine causes exaggerated reflexes and eventually tonic convulsions: your muscles tighten so you die with the risus sardonicus. Mutations in the glycine receptor that stop it working so well have an effect rather like strychnine. But rare though the disease is, at least 15 different mutations, each in a different family, have been found to produce similar effects. There is just one startle disease, but many.

Cystic fibrosis is even more complicated. Mutations in a single protein, with a function that is now quite well understood, can cause the disease. But every patient does not have the same mutation. Around 1500 mutations have been found in the 20 years since the gene was sequenced. And to make it still more complicated, the symptoms shown by two patients with the same mutation may not be identical. The effects depend, it seems, on the rest of the genetic make-up of the individual. There is a nice account in ‘The promise of a cure: 20 years and counting’..

The same pattern is repeated again and again. Schizophrenia is just a very extreme example of a common phenomenon Not so long ago it was the dogma was that the future of drug discovery lay in genomics and high-throughput screening, Richard Sykes, when head of GSK, put the vast resources of GSK into this approach. It did not really work (which might explain why he left GSK to become rector of Imperial College). Now we know why.

It turns out to be a bit more complicated than anyone had foreseen, and one suspects it will take a long time to sort it out.